The present invention relates to the targeting of radioactivity to a biomedical device and, in particular, to the use of radioimmunotherapy for the localization of radioactivity to stents for the reduction or elimination of restenosis.
Restenosis of blood vessels occurs after narrowed or occluded arteries are forcibly dilated by balloon catheters, drills, lasers and the like, in a procedure known as angioplasty. Such forcible dilation is required in order to reopen arteries which have been narrowed or occluded by atherosclerosis. However, up to 45% of all arteries which have been treated by angioplasty return to their narrowed state through the process of restenosis. Restenosis is caused both by recoil of the vessel wall towards its original dimensions and by neointimal hyperplasia induced by trauma to the vessel wall. Restenosis can significantly reduce the efficacy of angioplasty and as such is a major barrier to the effective treatment of narrowed arteries.
Attempts to reduce or eliminate restenosis have generally focused on the insertion of biomedical devices, such as stents, within the treated artery. Stents can reduce restenosis by preventing recoil of the treated blood vessel to its original dimensions. Various stents are known in the art, including coils and sleeves, those which are expandable by balloon catheters, heat expandable and self-expandable stents. Unfortunately, stents alone cannot prevent restenosis caused by neointimal hyperplasia of the tissues of the vessel wall. In fact, the stent material itself may accelerate such hyperplasia, since it is foreign to the body tissues.
Recently, as noted above, radionuclear irradiation of blood vessels has been proposed as a method of preventing restenosis caused by neointimal hyperplasia. The application of radionuclear irradiation to the body of a subject is a well accepted mode of therapy in medicine. The main use of such irradiation is for treating both malignant and benign tumors. Radionuclear irradiation can also be used to inhibit the undesired proliferation of cells in other rapidly growing tissues, such as keloids and blood vessels undergoing restenosis.
One study showed that such irradiation completely prevented restenosis of the treated arteries H. D. Bottcher et al., Int. J. Radiation Oncology Biol. Phys., 29:183-186, 1994!. A number of studies in animal models also support the efficacy of radionuclear irradiation of blood vessels for the prevention or reduction of restenosis following angioplasty J. G. Wiedermann et al., JACC, 23:1491-8, 1994; R. Waksman et al., Circulation, 92:3025-3031, 1995; R. Waksman et al., Circulation, 91:1533-1539, 1995!. Thus, clearly exposing the walls of blood vessels to radioactivity is a valuable method of preventing and treating restenosis caused by neointimal hyperplasia.
Currently, radionuclear irradiation of blood vessels is performed by the insertion of temporary or permanent radionuclear sources into the vessels. For example, radioactive yttrium-90 wires were inserted into the central lumen of a balloon catheter in order to irradiate blood vessel walls Y. Popowski et al., Int. J. Radiation Oncology Biol. Phys., 43:211-215, 1995!. Other radioactive sources have included iridium-192, administered by catheter to arteries which had been treated by angioplasty P. S. Teirstein et al., Circulation, 94:I-210, 1996!. U.S. Pat. No. 5,213,561 discloses a device for inserting a radionuclear source into a blood vessel, in which the source of radioactivity is mounted on a stent, for example.
Unfortunately, the insertion of radionuclear sources by a catheter or stent has a number of disadvantages. First, such procedures require a highly specialized clinical setting, which is appropriate both for catheterization procedures and for the handling of radioactivity. Second, these procedures are highly invasive. Third, temporary radioactive sources require repeated invasive treatments. However, temporary as well as permanent sources have the further disadvantage of decaying according to their specific half-life. Thus, current methods for irradiating blood vessels have significant disadvantages.
The concept of specifically targeting tumor cells is a goal of modern radio-oncology. The developing field of radiolabelled immunoglobulin therapy (RIT) employs radionuclide-labelled monoclonal antibodies which recognize tumor-associated antigens, thereby selectively targeting tumor cells. Beta particles emitted from a radiolabelled antibody bound to a tumor cell also kill neighboring cells because these particles can penetrate through several cell diameters. In B-cell lymphoma refractory to chemotherapy, RIT has been associated with a high rate of durable remissions Kaminki et al., JCO, 14:1974-1981, 1996!.
RIT may be effective for cancer treatment because tumor cells have special antigens on their surface, against which antibodies can be raised. Unfortunately, the situation is much more complicated for the prevention and treatment of restenosis. Restenotic tissue does not express special antigens, to that antibodies against such tissue would also bind to normal blood vessel walls and would not be sufficiently specific for the tissue to be treated. Thus, targeting antibodies directly to the tissue itself is not possible.
There is thus a widely recognized need for, and it would be highly advantageous to have, a method of targeting radioactivity to specific areas within a blood vessel or vessels, in order to perform localized radioimmunotherapy for treating or preventing restenosis of the vessel or vessels.